Repositioning of approved drugs and clinical-stage compounds with existing preclinical and clinical data can greatly expedite the process, particularly for rare, low-prevalence diseases and for rapidly-spreading infectious diseases, such as Zika virus. Through the drug repurposing screen, we have identified the anti-ZIKV and anti-Ebola virus activity of emetine, an anti-protozoal agent. Emetine potently inhibits ZIKV and EBOV infection with a low nanomolar half-maximal inhibitory concentration (IC50) in vitro and potent activity in animal models of ZIKV and Ebola virus infection. We also found two mechanisms of action for this drug, including the inhibition of ZIKV NS5 polymerase activity and disruption of lysosomal function. In addition, emetine inhibits EBOV entry into human cells. We also found that cephaeline, a desmethyl analog of emetine, exhibits a similar efficacy against both ZIKV and Ebola virus. Cephaeline may be more tolerable to patients than emetine with fewer adverse effects. Therefore, both emetine and cephaeline may have the potential to be advanced to clinical trials to treat infections caused by both ZIKV and Ebola virus. We have collaborated with Drs. Alexey Terskikh (Sanford Burnham Prebys Medical Discovery Institute), Hengli Tang (Florida State University) and Xiangguo Qiu (National Microbiology Laboratory, Public Health Agency of Canada) to test both emetine and cephaeline in the mouse models of ZIKV and Ebola virus infection. This research has been published in the journal of Cell Discovery (Yang et al., 2018). Based on our recent compound screening of 6000 bioactive compounds and approved drugs plus 90,000 diversity compounds using the ZIKV NS1 assay, our informatics expert developed several computational models to virtually screen and predict the anti-ZIKV NS1 activity of approximately 500,000 compounds in the NCATS compound collections. This work led to the identification of a number of new active compounds that suppressed ZIKV replication in cells. Further experiments confirmed about 20 selected compounds with inhibitory activities against ZIKV replication. These newly identified compounds, including known bioactive compounds and compounds with novel structures, showed potent inhibition of Zika viral replication. Because ZIKV and Dengue virus belong to the same flavivirus family, we tested these new compounds and found inhibitory activities against Dengue virus replication in a virus titer assay. These compounds can be potentially developed into new antiviral therapies against both ZIKV and Dengue virus infections. We are continuing to work on testing and optimizing these compounds, with the aim of further preclinical development. From our previous drug repurposing screen, Niclosamide, an anthelminthic drug, was found to inhibit ZIKV replication (Xu et al, Nature Medicine 2016). However, this approved drug has poor solubility in water and low oral bioavailability. We performed structure-activity relationship (SAR) and structure-properties relationship (SPR) studies of Niclosmaide. These efforts resulted in a new Niclosamide prodrug, TRND00507788, which has excellent solubility (>43 ug/mL at pH 7.4 buffer) and good oral bioavailability. We will continue to study and optimize this compound for its anti-ZIKV activity.